AZGP1 is androgen responsive and involved in AR‐induced prostate cancer cell proliferation and metastasis

• Published in: Journal of cellular physiology 2019-10, Vol.234 (10), p.17444-17458
• Main Authors: Cao, Runyi, Ke, Min, Wu, Qingxin, Tian, Qian, Liu, Li, Dai, Zao, Lu, Shan, Liu, Ping
• Format: Article
• Language: English
• Subjects: androgen; androgen receptor; Androgens; AZGP1; Cell adhesion & migration; Cell cycle; Cell growth; cell metastasis/invasion; Cell migration; Cell proliferation; Cyclin D1; Glycoproteins; Metastases; Metastasis; mRNA; Mutation; Phase transitions; Prostate cancer; S phase; Xenografts; Xenotransplantation; Zinc
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.28366

Alpha‐2‐glycoprotein 1, zinc‐binding (AZGP1), known as zinc‐alpha‐2‐glycoprotein (ZAG), is a multifunctional secretory glycoprotein and relevant to cancer metastasis. Little is known regarding the underlying mechanisms of AZGP1 in prostate cancer (PCa). In the present study, we report that AZGP1 is an androgen‐responsive gene, which is involved in AR‐induced PCa cell proliferation and metastasis. In clinical specimens, the expression of AZGP1 in PCa tissues is markedly higher than that in adjacent normal tissues. In cultures, expression of AZGP1 is upregulated by the androgen‐AR axis at both messenger RNA and protein levels. Furthermore, Chip‐Seq assay identifies canonical androgen‐responsive elements (AREs) at AZGP1 enhancer; and dual‐luciferase reporter assays reveal that the AREs is highly responsive to androgen whereas mutations of the AREs abolish the reporter activity. In addition, AZGP1 promotes G1/S phase transition and cell cycle progress by increasing cyclin D1 levels in PCa cells. Functional studies demonstrate that knocking down endogenous AZGP1 expression in LNCaP and CWR22Rv1 cells largely weaken androgen/AR axis‐induced cell migration and invasion. In vivo xenotransplantation tumor experiments also show that AZGP1 involves in androgen/AR axis‐mediated PCa cell proliferation. Taken together, our study implicates for the first time that AZGP1 is an AR target gene and is involved in androgen/AR axis‐mediated cell proliferation and metastasis in primary PCa. Androgen/androgen receptor (AR) axis regulates the expression of AZGP1 gene by AR binding on the enhancer of AZGP1 gene in prostate cancer (PCa) cells, and AZGP1 mediates the regulation of AR‐targeted genes and involves in AR‐regulated cell migration and invasion. We find that AZGP1 is a novel, downstream target gene of AR and plays an important role in androgen/AR axis‐regulated prostate carcinogenesis and progress of PCa.